What Are the Causes and Complications of Chronic Liver Disease and What Is the Evidence for Palliative Care Delivery to Those Affected by It?

Introduction and Scope of the Problem

Chronic liver disease (CLD) refers to a spectrum of hepatic conditions, including those that lead to reduced liver function, such as cirrhosis, and primary malignancies affecting the hepatobiliary system, most commonly hepatocellular carcinoma (HCC). This chapter focuses on cirrhosis. Though cirrhosis only affects less than 1% of the US population, it is a leading cause of mortality in the United States, with a 65% increase in deaths observed from 1999 to 2016. Patients with decompensated cirrhosis are also high utilizers of health care services, often experiencing frequent and long hospitalizations. Liver transplantation is the only curative treatment available to patients with decompensated cirrhosis, but the majority of patients are unable to receive a new organ, mostly due to insufficient organ availability and patient ineligbility. The end of life for patients with decompensated cirrhosis is complicated by frequent hospitalizations and higher use of life-sustaining treatments compared to other chronic conditions. Physical symptoms often are not well controlled, and caregivers report significant burden at the end of life. Small studies at North American liver transplant centers demonstrate that patients with advanced liver disease rarely receive palliative care consultations, even at the end of life. However, there is evidence of a trend toward increasing numbers of palliative care consultations for this population.

Palliative care practitioners may benefit from an understanding of the causes and trajectory of CLD because the resultant patient and family experience is profoundly affected by its complexity. The focus of this chapter is to provide a review of the epidemiology, pathophysiology, and natural history of CLD; standard management of the complications of CLD; estimation of prognosis; and liver transplantation. The small but growing evidence base for advance care planning and integration of palliative care into the care of people affected by CLD will be presented, along with models of care delivery.

Relevant Pathophysiology

Disorders Leading to Liver Disease

Cirrhosis is a chronic condition marked by extensive hepatic fibrosis, or deposition of collagen in the liver, as a response to liver injury over time. It is a common final pathway for several chronic liver diseases. Globally, the most common causes of cirrhosis are alcohol-associated liver disease and infections such as viral hepatitis B and hepatitis C. While the prevalence of hepatitis C is decreasing because of the advent of effective antiviral therapies, nonalcoholic steatohepatitis (NASH), a condition associated with metabolic syndrome and obesity, is on the rise. Progressive deposition of scar tissue, or fibrosis, leads to increased portal hypertension as well as decline in liver synthetic function as the functional liver tissue is replaced by scar tissue. Complications from portal hypertension result from both increased pressure throughout the portal venous circulation as well as the formation of shunts between the portal and systemic circulations; these events markedly reduce survival. “Decompensated cirrhosis” refers to disease associated with complications of portal hypertension (i.e., ascites, hepatic encephalopathy, variceal hemorrhage) while “compensated cirrhosis” refers to disease in the absence of such events. Decline in protein synthesis and metabolism also leads to dysfunction in the blood clotting cascade and production of immunoglobulins, which increases the risk of bleeding, thrombosis, and infection.

The majority of cases of CLD are due to alcohol-associated liver disease (ALD), viral hepatitis, and nonalcoholic fatty liver disease (NAFLD), which can lead to NASH. Less common causes of CLD include genetic and autoimmune etiologies.

Alcohol-Associated Liver Disease

Chronic excessive alcohol use results in several diseases, including alcohol-associated hepatitis, fatty liver disease, and cirrhosis. Additionally, alcohol can exacerbate hepatic damage in the setting of other CLDs. Mortality from ALD in the United States has markedly increased in recent years, with the most pronounced increase among people between the ages of 25 and 34 years. Chronic alcohol use can result in fibrosis that disrupts the liver architecture. The primary treatment of ALD is cessation of alcohol use combined with nutritional support. The 5-year survival rate of patients who continue to consume alcohol in the setting of cirrhosis is less than 50%. Transplantation is an option for those with advanced symptoms and liver failure. Traditionally, most transplant programs require alcohol-related counseling and abstinence from alcohol for a period of 6 months before being considered for transplant. However, more recently some centers will consider transplant for acute alcohol-associated hepatitis, in selected cases (see the section Liver Transplantation later in this chapter).

Viral Hepatitis

Chronic hepatitis B (HBV) and chronic hepatitis C (HCV) infections are the leading cause of CLD both in the United States and in the world. In the United States, chronic infections with hepatitis B and C are estimated at 1.59 million and 2.4 million people, respectively. Liver damage from viral hepatitis is likely immune mediated, which leads to the development of fibrosis and progression to cirrhosis. Antiviral treatment for HBV can effectively suppress, however rarely cure, HBV. The advent of direct-acting antivirals has revolutionized HCV treatment, with many regimens that offer cure rates of over 95% after only 3 months of a well-tolerated, once-daily pill.

Nonalcoholic Fatty Liver Disease

In the United States, NAFLD has a prevalence of 10% to 46% and is on track to become the most common indication for liver transplantation. Risk factors for NAFLD include obesity, diabetes, dyslipidemia, and hypertension. NAFLD consists of a spectrum of disorders: nonalcoholic fatty liver (NAFL) refers to steatosis without significant inflammation, while nonalcoholic steatohepatitis (NASH) is associated with steatosis and inflammation. Management largely includes treatment of underlying risk factors, including weight loss and optimal glycemic control. Previous studies of metformin as a potential therapy have not shown significant benefit, but there may be some benefit of vitamin E. NASH cirrhosis is a likely cause of cryptogenic cirrhosis in patients with metabolic syndrome.

Autoimmune Disorders

Autoimmune hepatitis (AIH) is an inflammatory condition associated with autoantibodies and elevated gamma globulins. It can present as fluctuations in liver enzymes, acute liver failure, and in some cases, cirrhosis. Management includes immunosuppressive medications such as immune modulators and steroids. Primary biliary cholangitis (PBC) results from immune-mediated destruction of small bile ducts. Symptoms commonly include fatigue, malabsorption due to fat-soluble vitamin deficiencies, and often severe pruritus, with case reports of patients attempting suicide as a result of the latter. Treatments of PBC include ursodeoxycholic acid and, more recently, obeticholic acid for patients without decompensated cirrhosis. Primary sclerosing cholangitis (PSC) is a condition of chronic inflammation and stricturing of the intra- and extrahepatic bile ducts. PSC is highly associated with ulcerative colitis (UC), with prevalence of UC as high as 90% among patients with PSC. Symptoms can range from asymptomatic to severe pruritus. Cholangiocarcinoma can develop in patients with PSC, with a lifetime risk of 10% to 15%. Unfortunately, drug therapy has not been shown to change the natural history of PSC. Management largely includes endoscopic interventions for symptomatic bile duct strictures.

Other Etiologies of Chronic Liver Disease

Several genetic disorders are associated with chronic liver disease and cirrhosis. Of note, the hereditary nature of these diseases means that families may often have multiple affected members facing the same serious illness. Wilson’s disease is an autosomal recessive disease that affects copper transport, resulting in copper accumulation in the liver and other organs such as the brain. Hereditary hemochromatosis, commonly associated with mutation in the HFE gene, results in tissue damage (often liver, heart, pituitary) from iron overload. Alpha 1 antitrypsin (AAT) deficiency is an inherited disorder that affects the lung and liver, presenting with early onset emphysema, neonatal hepatitis, and cirrhosis.

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